11-108353845-C-T

Variant names:

• chr11-108353845-C-T
• rs779858366
• NM_000051.4:c.8751C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PM2_Supporting BP4 BP7

This summary comes from the ClinGen Evidence Repository: The ATM c.8751C>T (p.Gly2917=) variant has a GnomAD (v2.1.1) allele frequency of 0.000%, which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). It is a synonymous variant (BP7). This variant is not predicted to impact splicing in multiple RNA in silico tools (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6266433/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: -0.259
• Publications: 3 publications found

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.8751C>T	p.Gly2917Gly	synonymous	Exon 60 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8751C>T	p.Gly2917Gly	synonymous	Exon 61 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.640+32075G>A		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.8751C>T	p.Gly2917Gly	synonymous	Exon 60 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.8751C>T	p.Gly2917Gly	synonymous	Exon 61 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*3815C>T		non_coding_transcript_exon	Exon 58 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74274

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	Ataxia-telangiectasia syndrome (1)
-	-	1	ATM-related cancer predisposition (1)
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.1
DANN	Benign	0.75
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779858366; hg19: chr11-108224572;